title: Functional complementation between FADD and RIP1 in embryos and lymphocytes.
abstract: FADD is a common adaptor shared by several death receptors for signalling apoptosis through recruitment and activation of caspase 8 (refs 1-3). Death receptors are essential for immune homeostasis, but dispensable during embryogenesis. Surprisingly, Fadd(-/-) mice die in utero and conditional deletion of FADD leads to impaired lymphocyte proliferation. How FADD regulates embryogenesis and lymphocyte responses has been a long-standing enigma. FADD could directly bind to RIP1 (also known as RIPK1), a serine/threonine kinase that mediates both necrosis and NF-κB activation. Here we show that Fadd(-/-) embryos contain raised levels of RIP1 and exhibit massive necrosis. To investigate a potential in vivo functional interaction between RIP1 and FADD, null alleles of RIP1 were crossed into Fadd(-/-) mice. Notably, RIP1 deficiency allowed normal embryogenesis of Fadd(-/-) mice. Conversely, the developmental defect of Rip1(-/-) lymphocytes was partially corrected by FADD deletion. Furthermore, RIP1 deficiency fully restored normal proliferation in Fadd(-/-) T cells but not in Fadd(-/-) B cells. Fadd(-/-)Rip1(-/-) double-knockout T cells are resistant to death induced by Fas or TNF-α and show reduced NF-κB activity. Therefore, our data demonstrate an unexpected cell-type-specific interplay between FADD and RIP1, which is critical for the regulation of apoptosis and necrosis during embryogenesis and lymphocyte function.
authors.affiliation: Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Haibing
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhou
authors.forename: Thomas
authors.initials: T
authors.lastname: McQuade
authors.forename: Jinghe
authors.initials: J
authors.lastname: Li
authors.forename: Francis Ka-Ming
authors.initials: FK
authors.lastname: Chan
authors.forename: Jianke
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D047108:Embryonic Development / Q000235:genetics; D053200:Fas-Associated Death Domain Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D005816:Genetic Complementation Test; D008214:Lymphocytes / Q000166:cytology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis / Q000235:genetics
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D020690:GTPase-Activating Proteins; C490620:Ralbp1 protein, mouse